Anemia is a frequent finding in patients with chronic kidney disease (CKD) and is present in over 90% of CKD patients with end-stage renal disease. Anemia typically results from inability of the diseased kidney to produce erythropoietin (EPO), which stimulates production of red blood cells. Anemia leads to fatigue, a decreased quality of life and correlates with increased mortality in CKD patients. Recombinant EPO is effective at reversing anemia in about 90% of CKD patients. Recombinant EPO products had worldwide sales of $11.6 billion in 2006 and are the single most expensive renal disease medicine in terms of total product sales. EPO has a short circulating half- life and generally is administered to patients two to three times per week. Bolder BioTechnology has created a highly potent, long-acting EPO analog that has a significantly increased circulating half-life and superior efficacy in animal erythropoiesis models compared to EPO. Based upon animal studies we anticipate that our long-acting EPO analog will be effective when administered once every 4-8 weeks in humans. The improved in vivo characteristics of this novel EPO analog will reduce the need for frequent injections, improve patient quality of life and potentially lead to improved therapeutic efficacy. Our long-acting EPO analog has the potential to significantly reduce healthcare costs by reducing the amount of drug required by patients, by reducing costs associated with patient visits to treatment centers and by reducing healthcare worker time associated with providing treatments. Because of its unique structure, manufacturing costs for our long-acting EPO analog are anticipated to be significantly less than for other EPO products. The goal of this proposal is to develop this long-acting EPO analog for the treatment of anemia associated with CKD. During Phase I of this proposal, we optimized the manufacturing process and developed and validated supporting assay methods to produce material for GLP (Good Laboratory Practices) pharmacology and toxicology studies. During Phase I we also designed clinical protocols for Phase 1 safety and Phase 2 dose ranging efficacy studies in humans. The main goal of the Phase II SBIR proposal is to complete the animal toxicology and pharmacology studies required by the FDA prior to testing this product in humans. Successful development of our long-acting EPO analog will provide CKD patients with a longer-acting, significantly less expensive alternative for the effective management of anemia. PUBLIC HEALTH RELEVANCE: Recombinant erythropoietin (EPO) is widely used to ameliorate anemia in patients with chronic kidney disease, which affects 20- 40 million people in the United States. EPO typically is administered to patients by twice weekly or thrice weekly injections due to its short half-life in people. We created longer acting and more potent EPO analogs that may potentially reduce the amount of EPO required per patient, improve patient safety, compliance and quality of life, and result in considerable cost savings to patients and healthcare providers. The goals of this Phase II grant proposal are to manufacture the protein under GLP (Good Laboratory Practices) conditions and measure the safety profile and pharmacokinetic properties of the protein in animal pharmacology and toxicology studies, which are required by the FDA prior to testing the compound in humans.